Impact of circadian nuclear receptor REV-ERBalpha on midbrain dopamine production and mood regulation.
*Affect; *Circadian Rhythm; Animals; Bipolar Disorder/genetics; CLOCK Proteins/genetics/metabolism; Cytoplasmic and Nuclear/genetics/*metabolism; Dopamine/*metabolism; Genetic; Group A; Histones/metabolism; Humans; Inbred C57BL; Knockout; Male; Member 2/metabolism; Mesencephalon/*metabolism; Mice; Mood Disorders/genetics/metabolism; Nuclear Receptor Subfamily 4; Rats; Receptors; Repressor Proteins/genetics/*metabolism; Transcription; Tyrosine 3-Monooxygenase/genetics
The circadian nature of mood and its dysfunction in affective disorders is well recognized, but the underlying molecular mechanisms are still unclear. Here, we show that the circadian nuclear receptor REV-ERBalpha, which is associated with bipolar disorder, impacts midbrain dopamine production and mood-related behavior in mice. Genetic deletion of the Rev-erbalpha gene or pharmacological inhibition of REV-ERBalpha activity in the ventral midbrain induced mania-like behavior in association with a central hyperdopaminergic state. Also, REV-ERBalpha repressed tyrosine hydroxylase (TH) gene transcription via competition with nuclear receptor-related 1 protein (NURR1), another nuclear receptor crucial for dopaminergic neuronal function, thereby driving circadian TH expression through a target-dependent antagonistic mechanism. In conclusion, we identified a molecular connection between the circadian timing system and mood regulation, suggesting that REV-ERBalpha could be targeting in the treatment of circadian rhythm-related affective disorders.
Chung Sooyoung; Lee Eun Jeong; Yun Seongsik; Choe Han Kyoung; Park Seong-Beom; Son Hyo Jin; Kim Kwang-Soo; Dluzen Dean E; Lee Inah; Hwang Onyou; Son Gi Hoon; Kim Kyungjin
Cell
2014
2014-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.cell.2014.03.039" target="_blank" rel="noreferrer noopener">10.1016/j.cell.2014.03.039</a>
Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis.
*Aldehyde Reductase/genetics/metabolism; Adenoviridae; Animal; Animals; Blood Glucose/*metabolism; Cholesterol/analysis; Cytoplasmic and Nuclear/genetics/*metabolism; Diabetes Mellitus/genetics/*metabolism/physiopathology; Disease Models; Fatty Liver/genetics/*metabolism/physiopathology; Gene Expression; Genetic Vectors; Gluconeogenesis/genetics; Homeostasis; Humans; Liver/*metabolism/physiopathology; Malondialdehyde/blood; Mice; Polymerase Chain Reaction; Receptors; Transfection; Transgenic; Triglycerides/analysis
Aldo-keto reductase 1B7 (AKR1B7) is proposed to play a role in detoxification of by-products of lipid peroxidation. In this article, we show that activation of the nuclear receptor farnesoid X receptor (FXR) induces AKR1B7 expression in the liver and intestine, and reduces the levels of malondialdehyde (MDA), the end product of lipid peroxidation, in the intestine but not in the liver. To determine whether AKR1B7 regulates MDA levels in vivo, we overexpressed AKR1B7 in the liver. Overexpression of AKR1B7 in the liver had no effect on hepatic or plasma MDA levels. Interestingly, hepatic expression of AKR1B7 significantly lowered plasma glucose levels in both wild-type and diabetic db/db mice, which was associated with reduced hepatic gluconeogenesis. Hepatic expression of AKR1B7 also significantly lowered hepatic triglyceride and cholesterol levels in db/db mice. These data reveal a novel function for AKR1B7 in lipid and glucose metabolism and suggest that AKR1B7 may not play a role in detoxification of lipid peroxides in the liver. AKR1B7 may be a therapeutic target for treatment of fatty liver disease associated with diabetes mellitus.
Ge Xuemei; Yin Liya; Ma Huiyan; Li Tiangang; Chiang John Y L; Zhang Yanqiao
Journal of lipid research
2011
2011-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1194/jlr.M015859" target="_blank" rel="noreferrer noopener">10.1194/jlr.M015859</a>
Nuclear receptors in bile acid metabolism.
Humans; Animals; Biological Transport; Bile Acids and Salts/*metabolism; Xenobiotics/metabolism/pharmacology; Receptors; Cytoplasmic and Nuclear/genetics/*metabolism; Inactivation; Metabolic
Bile acids are signaling molecules that activate nuclear receptors, such as farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and vitamin D receptor, and play a critical role in the regulation of lipid, glucose, energy, and drug metabolism. These xenobiotic/endobiotic-sensing nuclear receptors regulate phase I oxidation, phase II conjugation, and phase III transport in bile acid and drug metabolism in the digestive system. Integration of bile acid metabolism with drug metabolism controls absorption, transport, and metabolism of nutrients and drugs to maintain metabolic homeostasis and also protects against liver injury, inflammation, and related metabolic diseases, such as nonalcoholic fatty liver disease, diabetes, and obesity. Bile-acid-based drugs targeting nuclear receptors are in clinical trials for treating cholestatic liver diseases and fatty liver disease.
Li Tiangang; Chiang John Y L
Drug metabolism reviews
2013
2013-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3109/03602532.2012.740048" target="_blank" rel="noreferrer noopener">10.3109/03602532.2012.740048</a>
Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism.
*bile acid; *bile acid metabolism; *FXR; *Gene Expression Regulation; *GLP-1; *lipid metabolism; *liver metabolism; *non-alcoholic fatty liver disease; *obesity; *TGR5; *type 2 diabetes; Animals; Bile Acids and Salts/*biosynthesis/genetics; Cytoplasmic and Nuclear/genetics/*metabolism; Dietary Fats; G-Protein-Coupled/genetics/*metabolism; Glucagon-Like Peptide 1/genetics/metabolism; Glucose/metabolism; Knockout; Lipid Metabolism; Liver/*metabolism; Mice; Obesity/genetics/*metabolism/pathology; Receptors
The bile acid-activated receptors, nuclear farnesoid X receptor (FXR) and the membrane Takeda G-protein receptor 5 (TGR5), are known to improve glucose and insulin sensitivity in obese and diabetic mice. However, the metabolic roles of these two receptors and the underlying mechanisms are incompletely understood. Here, we studied the effects of the dual FXR and TGR5 agonist INT-767 on hepatic bile acid synthesis and intestinal secretion of glucagon-like peptide-1 (GLP-1) in wild-type, Fxr(-/-), and Tgr5(-/-) mice. INT-767 efficaciously stimulated intracellular Ca(2+) levels, cAMP activity, and GLP-1 secretion and improved glucose and lipid metabolism more than did the FXR-selective obeticholic acid and
Pathak Preeti; Liu Hailiang; Boehme Shannon; Xie Cen; Krausz Kristopher W; Gonzalez Frank; Chiang John Y L
The Journal of biological chemistry
2017
2017-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1074/jbc.M117.784322" target="_blank" rel="noreferrer noopener">10.1074/jbc.M117.784322</a>